Biotech Values

[DewDiligence]

SNY’s Otamixaban Is Unimpressive in Phase-2 ACS Trial

[The above header reflects my own opinion, which I think is borne out by the PR below. The 27-42% reduction in risk relative to the control arm in the primary endpoint sounds impressive, but: a) the lowest dose was excluded from the calculation; and b) no p-value is given in the PR. Moreover, otamixaban does not have a clean safety profile—as is the case with most anticoagulants, the efficacy comes at a cost in dose-dependent bleeding risk. Investors should want to know the bleeding risk of each individual dose, but these data are not given in the PR; instead, the PR combined the two middle doses of the six doses tested and asserts that the bleeding rate in these two arms was no worse than in the (unfractionated heparin + Integrillin) control arm.

Based on this PR, I cannot tell whether there are any dose(s) of otamixaban that warrant advancing the program into phase-3, but my suspicion is that there aren’t.

Otamixaban is several years behind some members of the class of oral FXa inhibitors: Xarelto from Bayer/JNJ is already approved in the EU for VTE and is in phase-3 for ACS, while Apixaban from BMY/PFE has completed a portion of its phase-3 program (#msg-40912878). SNY suggests in this PR that otamixaban is well suited to use in ACS because it has a short half-life; however, drugs that lack anti-thrombin (anti-FIIa) activity, a feature of all of the oral FXa inhibitors, have a built-in MoA disadvantage in ACS relative to Pradaxa, an oral inhibitor of thrombin that is already on the market in the EU (#msg-40912878). (MNTA’s M118 inhibits both FXa and thrombin, but is not oral.)

All told, I fail to see how SNY can differentiate otamixaban from the oral anticoagulants on the market and in development. If the decision were up to me, I would drop the program.

It’s notable that SNY hardly ever talks about otamixaban. I’ve never heard the drug discussed on SNY’s regular CC’s, and I had to go back almost two years to find a post on this board that mentions it.]

http://finance.yahoo.com/news/Study-Shows-Otamixaban-prnews-2175273349.html/print?x=0

›Study Shows Otamixaban Substantially Reduced Complications of Invasive Management of Acute Coronary Syndromes

Sunday August 30, 2009, 6:12 am EDT

- SEPIA-ACS Multiple-dose Phase II Results Showing 27- 42% Risk Reduction in ACS Complications Presented in Plenary Session of European Society of Cardiology Congress and Published in The Lancet

PARIS, August 30 /PRNewswire-FirstCall/ -- Sanofi-aventis (EURONEXT: SAN and NYSE: SNY) announced today that the investigational anti-Xa intravenous anticoagulant otamixaban reduced by 27 to 42 percent the odds of the composite primary endpoint of death, myocardial infarction, urgent revascularization or rescue GPIIb/IIIa use in 4 out of the 5 otamixaban tested doses [i.e. all doses but the lowest one, which was discontinued], versus standard UFH/eptifibatide combination [unfractionated heparin + Integrilin] in [non-ST] ACS patients suitable for invasive strategy. The results of the SEPIA-ACS1/ TIMI-42 were presented today at the plenary session of the Annual European Society of Cardiology congress in Barcelona and simultaneously published online in The Lancet.

Otamixaban is a first in class, rapid onset antithrombotic compound, acting as a direct selective inhibitor of factor Xa. Otamixaban is originating from Sanofi-aventis world-class thrombosis research portfolio and is currently in phase IIb clinical development phase.

"The data show that intermediate dosages of otamixaban may offer substantial reduction in major coronary complications in patients presenting with acute coronary syndrome, with bleeding rate comparable to current therapy," said Dr Marc Sabatine, MD, MPH, an Investigator in the TIMI Study Group and a cardiologist at Brigham and Women's Hospital, Harvard Medical School. "This research is addressing an important medical need, by potentially significantly improving outcomes of ACS patients undergoing PCI while simplifying the treatment pattern of the acute management phase of the disease." he added.

The double-blind phase II SEPIA-ACS1/ TIMI-42 study randomized 3241 patients from 36 countries in 6 treatment arms. The study assessed the efficacy and safety of five different doses of otamixaban versus the standard unfractionated heparin plus Glycoprotein IIb/IIIa inhibitor (eptifibatide), on background of standard dual antiplatelet therapy, in patients with high-risk non-ST-elevation acute coronary syndromes. SEPIA-ACS1 study showed that otamixaban displayed clinically meaningful activity on the primary endpoint from the threshold dose of 0.070 mg/kg/h, the second tested dose, with a consistent antithrombotic effect up to the 5th highest tested dosage. The lowest studied dosage was prematurely stopped due to insufficient activity, based on recommendation by an independent data monitoring board. Moreover. a combined analysis of the intermediate doses (0.105 and 0.140 mg/kg/h) of otamixaban arms showed that otamixaban reduced by approximately 46 percent (p=0.0198) the risk of the composite of death or a second myocardial infarction, a predefined study secondary efficacy endpoint [However, combining two of the six doses in this post hoc manner does not make for a compelling finding.]

The potent antithrombotic effect of otamixaban was also accompanied with a dose-dependent bleeding profile. Combined intermediate otamixaban dosages showed a safety profile not statistically different with regard to TIMI major or minor bleeding through 7 days, in comparison to UFH and GPIIb/IIIa inhibitor comparator (RR 1.20, 95% CI 0.64-2.27, p=0.5634). [A breakdown of the bleeding data by dose is highly relevant, obviously; that such data are not given in this PR is a red flag.]

"The SEPIA-ACS1 trial is providing very encouraging results for a new and more effective treatment approach," said Marc Cluzel, MD Senior Vice President Research and Development Sanofi-aventis. "We aim, on the basis of these findings to address through our development program remaining patients', practionners' and payers' needs for management of ACS."

Acute Coronary Syndromes is a general term used to regroup clinical symptoms related to acute myocardial ischemia. ACS represents an area of important medical need, as despite use of several antithrombotic therapies, death and myocardial infarction still occur in 5 to 8% of patients in the following week after an initial event.‹